Tumors are dependent upon new blood vessel formation, or angiogenesis, for expansive growth. Our prior analysis of gene expression led to the identification of several genes upregulated in endothelial cells that line tumor blood vessels, called TEMs. Two of these, TEM5 and TEM8 encode products that are of particular interest because they reside on the cell surface and may therefore be directly accessible to blood-borne therapeutics. In an attempt to understand the functional role of these genes in angiogenesis, we have generated TEM5 and TEM8 knockout mice. By challenging the gene disrupted mice with tumors, we are evaluating the importance of these genes in tumor angiogenesis. These studies are also enabling us to better understand the normal physiological function of these genes particularly as it relates to angiogenesis.